Pa Tho Physiology of Traumatic Brain Injury2

8/3/2019 Pa Tho Physiology of Traumatic Brain Injury2

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Pathophysiology of traumaticPathophysiology of traumatic

brain injurybrain injury

C. Werner* and K. Engelhard Klinik frAnsthesiologie, der Johannes Gutenberg-Universitt Mainz, Langenbeckstrasse 1,

D-55131 Mainz, Germany


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IntroductionIntroduction

The leading cause of morbidity andmortality in individuals under the age of 45yr in the world

TBI predominantly derived from clinical

work with particular emphasis on cerebralblood flow (CBF) and metabolism, cerebraloxygenation, excitotoxicity, oedemaformation, and inflammatory processes.


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Biomechanical andBiomechanical and

neuropathological classification ofneuropathological classification of

injuryinjuryThe principal mechanisms of TBI are

classified as:

(a) focal brain damage due to contactinjury types resulting in contusion,

laceration, and intracranial haemorrhage(b) diffuse brain damage due toacceleration/deceleration injury typesresulting in diffuse axonal injury or brain

swelling


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Outcome from head injury is determined bytwo substantially different

mechanisms/stages:(a) the primary insult (primary damage,mechanical damage) occurring at themoment of impact. In treatment terms, this

type of injury is exclusively sensitive topreventive but not therapeutic measures.

(b) The secondary insult (secondarydamage, delayed non-mechanical damage)

represents consecutive pathologicalprocesses initiated at the moment of injurywith delayed clinical presentation


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General pathophysiology ofGeneral pathophysiology of

traumatic brain injurytraumatic brain injury

1. Cerebral injury after TBI are characterized by direct tissue

damage and impaired regulation of CBF and metabolism

This ischaemia-like pattern leads to accumulation of

lactic acid due to anaerobic glycolysis, increasedmembrane permeability, and consecutive oedema

formation. Since the anaerobic metabolism is inadequate

to maintain cellular energy states, the ATP-stores deplete

and failure of energy-dependent membrane ion pumpsoccurs


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2. Pathophysiological cascade is characterized by terminalmembrane depolarization along with excessive release ofexcitatory neurotransmitters (i.e. glutamate, aspartate),

activation ofN-methyl-D-aspartate, -amino-3-hydroxy-5-

methyl-4-isoxazolpropionate, and voltage-dependent Ca2+-

and Na+-channels.The consecutive Ca2+- and Na+-influx leads to self-digesting

(catabolic) intracellular processes. Ca2+ activates lipid

peroxidases, proteases, and phospholipases which in turn

increase the intracellular concentration of free fatty acids and

free radicals.

These events lead to membrane degradation of vascular and

cellular structures and ultimately necrotic or programmed cell

death (apoptosis).


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The frequent association between cerebral

hypoperfusion and poor outcome suggests thatTBI and ischaemic stroke share the samefundamental mechanisms.

Although this assumption may be true to some

extent, major differences

exist between thesetwo different types of primary injury. For

example, the critical threshold of CBF for thedevelopment ofirreversible tissue damage is 15

ml 100 g1

min1

in patients with TBI comparedwith 58.5 ml 100 g1 min1 in patients withischaemic stroke


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While cerebral ischaemia predominantly leads tometabolic stress and ionic perturbations, headtrauma additionally exposes the brain tissue toshear forces with consecutive structural injury ofneuronal cell bodies, astrocytes, and microglia,

and cerebral microvascular and endothelial celldamage.The mechanisms by which post-traumatic

ischaemia occurs include morphological injury(e.g. vessel distortion) as a result of mechanicaldisplacement, hypotension in the presence of

autoregulatory failure, inadequate availability ofnitric oxide or cholinergic neurotransmitters,and

potentiation of prostaglandin-inducedvasoconstriction.


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Patients with TBI may develop cerebral hyperperfusion (CBF >55ml 100 g1 min1) in the early stages of injury.

This pathology seems as detrimental as ischaemia interms ofoutcome because increases in CBF beyond matching metabolic

demand relate to vasoparalysis with consecutive increases in

cerebral blood volume and in turn intracranial pressure (ICP) It is important to note that diagnosing hypoperfusion or

hyperperfusion is only valid after assessing measurements of CBF

in relation to those of cerebral oxygen consumption. Both cerebral ischaemia and hyperaemia refer to a mismatch

between CBF and cerebral metabolism. For example, low flow with normal or high metabolic

rate represents an ischaemic situation whereas highCBF withnormal or reduced metabolic raterepresents cerebral hyperaemia.In contrast, low CBFwith a low metabolic rate or highCBF with highmetabolic rates represents coupling between flow

and metabolism, a situation that does notnecessarily reflecta pathological condition.


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Cerebrovascular autoregulation and CO2-reactivityCerebrovascular autoregulation and CO2-reactivity

Cerebrovascular autoregulation and CO2-reactivity are important mechanisms to provideadequate CBF at any time. Likewise, both

patterns are the basis for the management of

cerebral perfusion pressure (CPP) and ICP andimpairment of these regulatory mechanismsreflect increased risk for secondary braindamage.After TBI, CBF autoregulation (i.e.

cerebrovascular constriction or dilation inresponse to increases or decreases in CPP) isimpaired or abolished in most patients


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The temporal profile of this pathology is asinconsistent as the severity of injury to produce

autoregulatory failure. Defective CBF autoregulationmay be present immediately after trauma or maydevelop over time, and is transient or persistent innature irrespective of the presence of mild,moderate, or severe damage

Compared with CBF autoregulation, cerebrovascularCO2-reactivity(i.e. cerebrovascular constriction or

dilation in response tohypo- or hypercapnia) seemsto be a more robust phenomenon.In patients withsevere brain injury and poor outcome, CO2-reactivity

is impaired in the early stages after trauma.

Incontrast,CO2-reactivity was intact or even enhancedin most other patientsoffering this physiologicalprinciple as a target for ICP managementinhyperaemic states


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Cerebral vasospasmCerebral vasospasmVasospasm occurs in more than one-third of patients

with TBI and indicates severe damage to the brain.The onset varies from post-traumatic day 2 to 15 and

hypoperfusion(haemodynamically significantvasospasm) occurs in 50% of allpatients developing

vasospasmThe mechanisms by which vasospasmoccurs includeChronic depolarization of vascular smooth muscledue to reduced potassium channel activity,release ofendothelin along with reduced availability of nitric

oxide, cyclic GMP depletion of vascular smoothmuscle,potentiation of prostaglandin-inducedvasoconstriction,and free radical formation.


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2. Cerebral oxygenation2. Cerebral oxygenation

TBI is characterized by an imbalance between cerebral

oxygen delivery and cerebral oxygen consumption

Measurements of brain tissue oxygen pressure in patients

suffering from TBI have identified the critical thresholdof 1510 mm HgPtO2 below which infarction of

neuronal tissue occurs

Oxygen deprivation of the brain with consecutive

secondary brain damage may occur even in the presenceof normal CPP or ICP


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33.. Excitotoxicity and oxidative stressExcitotoxicity and oxidative stress

TBI is primarily and secondarily associated with amassive release of excitatory amino acidneurotransmitters, particularly glutamate.

This excess in extracellular glutamate availabilityaffects neurons and astrocytes and results in over-

stimulation of ionotropic and metabotropic glutamatereceptors with consecutive Ca2+, Na+, and K+-fluxesAlthough these events trigger catabolicprocesses

including bloodbrain barrier breakdown, thecellularattempt to compensate for ionic gradients increases

Na+/K+-ATPase activity and in turn metabolic demand,creatinga vicious circle of flowmetabolism uncouplingto thecell.


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Oxidative stress relates to the generation of reactive oxygen

species (oxygen free radicals and associated entities includingsuperoxides, hydrogen peroxide, nitric oxide, andperoxinitrite) in response to TBI

The excessive production of reactive oxygen species due toexcitotoxicity and exhaustion of the endogenous antioxidant

system (e.g. superoxide dismutase, glutathione peroxidase,and catalase) induces peroxidation of cellular and vascularstructures, protein oxidation, cleavage of DNA, and inhibitionof the mitochondrial electron transport chain.

These mechanisms are adequate to contribute to immediatecell death, inflammatory processes and early or late apoptotic

programmes are induced by oxidative stress.


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4. Oedema4. Oedema

The current classification of brain oedema relates to thestructural damage or water and osmotic imbalanceinduced by the primary or secondary injury

Vasogenic brain oedema : is caused by mechanical orautodigestive disruption or functional breakdown of the

endothelial cell layer (an essential structure of the bloodbrain barrier) of brain vessels. Disintegration of thecerebral vascular endothelial wall allows for uncontrolledion and protein transfer from the intravascular to theextracellular (interstitial) brain compartments withensuring water accumulation. Anatomically, this

pathology increases the volume of the extracellular space.


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The additional release of vasoconstrictors

(prostaglandins and leucotrienes), the

obliteration of microvasculature through

adhesion of leucocytes and platelets, the

bloodbrain barrier lesion, and the oedema

formation further reduce tissue perfusion

and consequently aggravate secondarybrain damage.


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Necrosis vs apoptosisNecrosis vs apoptosis

Necrosis occurs in response to severe mechanical orischaemic/hypoxic tissue damage with excessiverelease of excitatory amino acid neurotransmitters andmetabolic failure. Subsequently, phospholipases,proteases, and lipid peroxidases autolyse biologicalmembranes

Apoptosis becomes evident hours or days after theprimary insult. Translocation of phosphatidylserine

initiates discrete but progressive membranedisintegration along with lysis of nuclear membranes,chromatine condensation, and DNA-fragmentation


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Summary and conclusionSummary and conclusion

TBI combines mechanical stress to brain tissue with animbalance between CBF and metabolism, excitotoxicity,oedema formation, and inflammatory and apoptotic

processesUnderstanding the multidimensional cascade of injury

offers therapeutic options including the management ofCPP, mechanical (hyper-) ventilation, kinetic therapy toimprove oxygenation and to reduce ICP, and

pharmacological intervention to reduce excitotoxicity andICP

Yet, the unpredictability of the individual'spathophysiology requires monitoring of the injured brainin order to tailor the treatment according to the specificstatus of the patient

Documents

Pa Tho Physiology of Traumatic Brain Injury2